The core group of users at the Kimmel Cancer Center of Thomas Jefferson University proposes to acquire a BIAcore 3000 surface plasmon resonance biosensor. We have been using an IAsys Resonant Mirror Biosenser (Affinity Sensor) as the core instrument of the Molecular Interactions Facility to measure the kinetics of biomolecular interactions. While this instrument has allowed the users to execute successfully a number of projects, new and more challenging experiments will require a more sophisticated instrument. The BIAcore 3000 provides approximately 10-fold lower noise than the IAsys, yielding much greater sensitivity and permitting detection of the binding of low molecular weight ligands, not just macromolecules. The BIAcore 3000 also provides more precise temperature stabilization (q0.IxC vs. q0.30C at best) and 2-times wider temperature range, which is essential for accurate thermodynamic analysis of biomolecular interactions. The BIAcore 3000 is capable of measuring the widest range of refractive indexes and has superior Global software for data analysis. In addition, the single instrument we currently have in the Molecular Interaction Facility cannot accommodate the growing number of users. With a modem biosensor such as the BIAcore 3000, the core users will be able to address comprehensively the following questions: 1. What molecular mechanisms dictate the specificity of antigen-specific receptors, as revealed by the thermodynamics of their reactions with cognate antigens? Differences in their mechanisms will be related to differences in the universe of antigens recognized by B-cell and T-cell receptors; 2. How do protein-protein and protein-DNA interactions guide DNA repair? We must determine how mutations in DNA repair genes permit carcinogenesis; 3. How do protein-protein and protein-DNA interactions guide site-specific gene transposition? Understanding the accuracy of this process is a prerequisite to applying site-specific transposition for gene therapy; 4. How do 5-Helix and C-peptide inhibitors interact with gp41 to block HIV-1 entry? We must understand their mechanisms in order to design stable small molecule-therapeutics; 5. Can the interactions between cyclic peptide ligands and their receptors help to explain the effect of those ligands on cell physiology? We must understand ligand-receptor interactions to validate new targets and characterize new therapeutics.